This proposal addresses itself to causes of lysosomal alterations seen in hypertensive vascular smooth muscle and their relationship to cell wall damage. The underlying hypothesis is that some serum substances enter vascular smooth muscle cells due to a permeable intimal layer and these substances (perhaps serum proteinase inhibitors) impair the digestive processes of lysosomes by inhibition of lysosomal enzymes such as cathepsin D. The results of such impaired function are vascular smooth muscle cells whose lysosomes are swollen and which resemble those seen in Hurler's disease and atherosclerosis but which apparently contain different substances. We plan to study these lysosomal alterations by tissue fractionation techniques, biochemical enzyme analyses and cytochemical enzyme localizations in normotensive and spontaneously hypertensive rat vascular smooth muscle. Also, to elucidate the role of impaired protein degradative capacity in the formation of these abnormal lysosomes, we will induce inhibition of proteinases in vivo by the use of the lysosomotrophic drug, chloroquine. These results should help define the cause of lysosomal alteration following hypertension and the extent to which these changes cause vascular lesions and smooth muscle cell death.